Endothelial cells are highly dependent on tubulin cytoskeleton for their motility, invasion, attachment, alignment and proliferation. Vascular disrupting agents (VDAs), a new class of agents, target endothelial cells and pericytes of the already established tumor vasculature. Most VDAs induce changes in endothelial cell shape by disruption of the cytoskeleton and cell-to-cell junctions. This results in increased permeability to proteins and an increased interstitial fluid pressure, which might be sufficient to reduce vessel diameter. Plasma leakage also leads to increased blood viscosity resulting in decreased blood flow and rouleaux formation. Another factor contributing to the vascular shutdown is the activation of platelets through contact with basement membrane components, which are exposed. All together this cascade of events results in vascular shutdown more selectively in tumor endothelium than normal endothelium. It is suggested that the inhibition of blood flow and the subsequent compromised supply of oxygen and nutrients will induce necrosis of many tumor cells downstream.
Vascular disrupting agents have been divided into two types, small molecule and ligand directed VDAs. Small molecule VDAs are in a more advanced stage of clinical development. Small molecule VDAs are either tubulin-binding agents or flavonoids. Tubulin-binding agents work by acting at the colchicine-binding site of the β-subunit of endothelial tubulin, resulting in depolymerization of microtubules and disorganization of actin and tubulin (e.g. combretastatin). Disruption of the endothelial cytoskeleton results in conformational changes leading to loss of blood flow. Tumor-related endothelial cells are much more sensitive to the activity of tubulin-binding agents than normal endothelial cells.
Clinical studies investigating the efficacy of VDAs, however, have not been able to meet objectives for increases in overall survival or 6 month progression free survival across patient populations.